When this project started (1980), the universal view was that the efficacy of ECT depended only on the generalized seizure, while its cognitive effects were largely determined by the electrical stimulation. Yet, standard practice often involved treating all patients at the device maximum. Introducing the methods to titrate dosage, and over the course of 4 randomized trials, we demonstrated marked individual differences in seizure threshold (ST) and showed that right unilateral (RUL) ECT's efficacy is highly dependent on dosage relative to ST. In our 2 most recent studies, high dosage RUL ECT (6xST) equaled the efficacy of a robust form of bilateral (BL) ECT (2.5xST), yet retained advantages in cognitive side effects. The soon completed Study 4 also tested the view that the traditional ECT stimulus is non-physiologic, delivering energy long after neuronal depolarization. In a comparison of BL and RUL ECT, each given with a standard (1.5 ms) or ultrabrief (0.3 ms) pulse width (PW), our preliminary data shows that: (1) Ultrabrief stimulation is 3-4 times more efficient; (2) Its generalized seizures have weak EEG expression, but this has little bearing on efficacy; (3) ultrabrief RUL ECT (6xST) is highly effective; (4) But ultrabrief BL ECT (2.5xST) has poor efficacy; and (5) the cognitive advantages of ultrabrief ECT are profound, greater than the differences between RUL and BL ECT. Study 5 will both replicate key findings and test 2 novel innovations: use of a unidirectional waveform and spatial targeting to restrict seizure onset to right prefrontal cortex. Using a randomized 2x2 factorial design, we aim to (1) Replicate the advantages of ultrabrief stimulation and (2) Demonstrate that spatial targeting results in substantial additive benefit (2 main effects). We predict that these modifications reduce the cognitive burden of ECT, and also have superior effects on functional, subjective, and neurophysiological outcomes. The preliminary data suggest that ultrabrief RUL ECT is highly effective, yet produces negligible amnesia, even when patients, tested a few days after ECT, are compared to healthy controls. Confirming this benefit and demonstrating that spatial targeting further reduces cognitive burden should have fundamental impact on ECT practice.